Mendelian Randomization and Transcriptome-Wide Association Analysis Identified Genes That Were Pleiotropically Associated with Intraocular Pressure

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2023 May 27

PMID 37239387

Authors

Zhikun Yang

Zhewei Zhang

Yining Zhu

Guangwei Yuan

Jingyun Yang

Weihong Yu

Affiliations

Soon will be listed here.

Abstract

Background: Intraocular pressure (IOP) is a major modifiable risk factor for glaucoma. However, the mechanisms underlying the controlling of IOP remain to be elucidated.

Objective: To prioritize genes that are pleiotropically associated with IOP.

Methods: We adopted a two-sample Mendelian randomization method, named summary-based Mendelian randomization (SMR), to examine the pleiotropic effect of gene expression on IOP. The SMR analyses were based on summarized data from a genome-wide association study (GWAS) on IOP. We conducted separate SMR analyses using Genotype-Tissue Expression (GTEx) and Consortium for the Architecture of Gene Expression (CAGE) expression quantitative trait loci (eQTL) data. Additionally, we performed a transcriptome-wide association study (TWAS) to identify genes whose cis-regulated expression levels were associated with IOP.

Results: We identified 19 and 25 genes showing pleiotropic association with IOP using the GTEx and CAGE eQTL data, respectively. (P = 2.66 × 10), (P = 2.78 × 10), and (P = 2.91 × 10) were the top three genes using the GTEx eQTL data. (P = 1.19 × 10), (P = 1.19 × 10), and (P = 1.53 × 10) were the top three genes using the CAGE eQTL data. Most of the identified genes were found in or near the 17q21.31 genomic region. Additionally, our TWAS analysis identified 18 significant genes whose expression was associated with IOP. Of these, 12 and 4 were also identified by the SMR analysis using the GTEx and CAGE eQTL data, respectively.

Conclusions: Our findings suggest that the 17q21.31 genomic region may play a critical role in the regulation of IOP.

Citing Articles

NR0B2 Is a Key Factor for Gastric Diseases: A GEO Database Analysis Combined with Drug-Target Mendelian Randomization.

Li Z, Xu L, Huang D, Li C, Haenen G, Zhang M Genes (Basel). 2024; 15(9).

PMID: 39336801 PMC: 11431353. DOI: 10.3390/genes15091210.

Causal Associations of Glaucoma and Age-Related Macular Degeneration with Cataract: A Bidirectional Two-Sample Mendelian Randomisation Study.

Seo J, Lee Y Genes (Basel). 2024; 15(4).

PMID: 38674349 PMC: 11049509. DOI: 10.3390/genes15040413.

Transcriptome-wide association studies: recent advances in methods, applications and available databases.

Mai J, Lu M, Gao Q, Zeng J, Xiao J Commun Biol. 2023; 6(1):899.

PMID: 37658226 PMC: 10474133. DOI: 10.1038/s42003-023-05279-y.

References

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

Vuong T, Lee S, Leem Y, Lee J, Bae G, Kang J . SGTb regulates a surface localization of a guidance receptor BOC to promote neurite outgrowth. Cell Signal. 2019; 55:100-108. DOI: 10.1016/j.cellsig.2019.01.003. View

ARMALY M, KRUEGER D, Maunder L, Becker B, Hetherington Jr J, Kolker A . Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field defects. Arch Ophthalmol. 1980; 98(12):2163-71. DOI: 10.1001/archopht.1980.01020041015002. View

de Jong S, Chepelev I, Janson E, Strengman E, van den Berg L, Veldink J . Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner. BMC Genomics. 2012; 13:458. PMC: 3582489. DOI: 10.1186/1471-2164-13-458. View

Yang Z, Yang J, Liu D, Yu W . Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness. BMC Genomics. 2021; 22(1):517. PMC: 8263012. DOI: 10.1186/s12864-021-07860-3. View

Bennett E, Steffensen R, Clausen H, Weghuis D, Geurts van Kessel A . Genomic cloning of the human histo-blood group ABO locus. Biochem Biophys Res Commun. 1995; 211(1):347. DOI: 10.1006/bbrc.1995.1817. View

Qian Y, Baisden J, Zot H, Van Winkle W, Flynn D . The carboxy terminus of AFAP-110 modulates direct interactions with actin filaments and regulates its ability to alter actin filament integrity and induce lamellipodia formation. Exp Cell Res. 2000; 255(1):102-13. DOI: 10.1006/excr.1999.4795. View

Strunz T, Kiel C, Grassmann F, Ratnapriya R, Kwicklis M, Karlstetter M . A mega-analysis of expression quantitative trait loci in retinal tissue. PLoS Genet. 2020; 16(9):e1008934. PMC: 7462281. DOI: 10.1371/journal.pgen.1008934. View

Gharahkhani P, Burdon K, Fogarty R, Sharma S, Hewitt A, Martin S . Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet. 2014; 46(10):1120-1125. PMC: 4177327. DOI: 10.1038/ng.3079. View

10.

Springelkamp H, Iglesias A, Mishra A, Hohn R, Wojciechowski R, Khawaja A . New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. Hum Mol Genet. 2017; 26(2):438-453. PMC: 5968632. DOI: 10.1093/hmg/ddw399. View

11.

Gedde S, Vinod K, Wright M, Muir K, Lind J, Chen P . Primary Open-Angle Glaucoma Preferred Practice Pattern®. Ophthalmology. 2021; 128(1):P71-P150. DOI: 10.1016/j.ophtha.2020.10.022. View

12.

Li S, Schooling C . A phenome-wide association study of ABO blood groups. BMC Med. 2020; 18(1):334. PMC: 7669452. DOI: 10.1186/s12916-020-01795-4. View

13.

Winnefeld M, Rommelaere J, Cziepluch C . The human small glutamine-rich TPR-containing protein is required for progress through cell division. Exp Cell Res. 2004; 293(1):43-57. DOI: 10.1016/j.yexcr.2003.09.028. View

14.

Cooke Bailey J, Loomis S, Kang J, Allingham R, Gharahkhani P, Khor C . Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet. 2016; 48(2):189-94. PMC: 4731307. DOI: 10.1038/ng.3482. View

15.

Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx B . Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016; 48(3):245-52. PMC: 4767558. DOI: 10.1038/ng.3506. View

16.

Suriyapperuma S, Child A, Desai T, Brice G, Kerr A, Crick R . A new locus (GLC1H) for adult-onset primary open-angle glaucoma maps to the 2p15-p16 region. Arch Ophthalmol. 2007; 125(1):86-92. DOI: 10.1001/archopht.125.1.86. View

17.

Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, De Pooter T . Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet. 2005; 14(13):1753-62. DOI: 10.1093/hmg/ddi182. View

18.

Sanfilippo P, Hewitt A, Hammond C, Mackey D . The heritability of ocular traits. Surv Ophthalmol. 2010; 55(6):561-83. DOI: 10.1016/j.survophthal.2010.07.003. View

19.

Bonovas S, Filioussi K, Tsantes A, Peponis V . Epidemiological association between cigarette smoking and primary open-angle glaucoma: a meta-analysis. Public Health. 2004; 118(4):256-61. DOI: 10.1016/j.puhe.2003.09.009. View

20.

Pierce B, Burgess S . Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013; 178(7):1177-84. PMC: 3783091. DOI: 10.1093/aje/kwt084. View